The dimeric Catharantus (Vinca) alkaloids vinblastine and vincristine have been shown to be extremely efficacious, clinically useful anticancer agents. The isolation and purification of these naturally occurring compounds from catharanthus roseus is a difficult process. Recently, approaches have been reported for the preparation of semi-synthetic dimeric vinblastine/vincristine-type alkaloids by the coupling of naturally occurring and readily available vindoline with catharanthine derivatives. Thse approaches are unfortunately limited by the relative inaccessibility of naturally occurring catharanthine. The objective of the proposed research is to develop a short and highly efficient total synthesis of catharanthine by a procedure which woould be flexible enough to prepare a variety of analogs as well. The key step in the proposed synthesis involves the Diels-Alder reaction of a dihydropyridine to given an isoquinucleodine with the requisite functionality for elaboration to catharanthine. In preliminary studies we have already demonstrated the feasibility of preparing the necessary isoquinucleodine by this process. The specific aims of the proposed research include a continuation of studies to optimize conditions for the preparation of the crucial isoquinucleodine intermediate, an examination of several synthetic plans for the conversion of this intermediate to catharathine, an investigation directed toward the enantiospecific synthesis of the isoquinucleodine by the use of appropriate chiral precursors, and a completion of the synthesis of a number of catharanthine analogs which would be useful for the preparaton of semi-synthetic vincristine, vinblastine, and related analogs.